Diabetes is a series of metabolism disorder syndromes of sugar, protein, lipid, water, electrolyte and the like, due to hypoinsulinism, insulin resistance and the like, resulted from the action of various pathogenic factors on the body, including hereditary factors, immune disorder, microbiological infection and the toxins thereof, free radical toxins and psychic factors etc. Clinically, diabetes is mainly characterized by hyperglycemia, in which manifestations, such as diuresis, polydipsia, polyphagia and emaciation (i.e., “three enhancements and one reduction” in symptoms) etc. may appear in typical cases. Once diabetes (blood sugar) is not well controlled, complications may occur, which result in incurable failure and lesions in kidney, eye and foot.
Diabetes can be divided into type I diabetes, type II diabetes, gestational diabetes and other special types of diabetes. Type II diabetes accounts for about 95% of all the diabetic patients. Type I diabetes is a kind of autoimmune disease, resulted from the attack on the body by the immune system itself. The pancreatic beta cells of the diabetic patient, by which insulin is secreted, are attacked and killed by his own immune system, leading to insufficient insulin secreted by the pancreas. Type I diabetes mostly occurs in adolescents, who will rely on exogenous insulin supplemented to maintain their lives, due to the lack of insulin secreted. Type II diabetes exhibits stronger heritability and environmental factors, and has significant heterogeneity. At present, it is believed that the pathogenesis of diabetes is a combination of insulin resistance (mainly manifested as hyperinsulinemia and low glucose utilization) and hypoinsulinism, and as a result, the manifestations of diabetes are not always the same, in which in some cases insulin resistance dominates accompanied with hypoinsulinism, while in other cases hypoinsulinism dominates accompanied with or without insulin resistance.
Exenatide, as shown in Formula I, has an amino acid sequence of SEQ ID No. 2, which is the first incretin analog developed by Eli Lilly and Company (USA) together with Amylin Company. Exenatide is a synthetic polypeptide composed of 39 amino acids, which has similar effects as an endogenous incretin such as glicetin-1 (GLP-1), including promoting glucose-dependent insulin secretion, restoring first-phase insulin secretion, inhibiting glucagon secretion, slowing the evacuation of gastric contents, and improving the function of pancreatic beta cells. In 2004, exenatide has been approved for marketing by FDA under the trade name Byetta. It is a subcutaneous injection formulation administrated twice a day.
The application has been approved by US Food and Drug Administration (FDA) on Jan. 27, 2012 for marketing of the controlled release formulation (once a week) of exenatide injection. The control of blood sugar can be improved by using such a formulation for adult patients of type II diabetes on the basis of diet and exercise. This is the first therapeutic drug for type II diabetes administered weekly.
This peptide was synthesized by single solid-phase sequential coupling methods as described in U.S. Pat. No. 6,924,264, U.S. Pat. No. 7,157,555, U.S. Pat. No. 6,902,744 and CN101357938A. Using amine resin as the carrier, exenatide was obtained by sequential coupling and final cleavage. However, since the amino acid at the N-terminal is His, racemic impurities of His, which is difficult to be removed by purification, may be created by using the routine coupling material Fmoc-His(Trt)-OH and the coupling methods in the Fmoc solid phase synthesis.
